Decreased production of estrogen in the postmenopausal women leads to symptoms such as osteoporosis and fat liver, etc. Estrogen replacement therapy has been utilized to treat these symptoms and showed an increased risk of breast and uterine cancers. Marketed as an antagonist of estrogen receptor (ER) to treat ER+ breast cancer patients, tamoxifen also induces de novo or acquired tamoxifen resistance resulting in the discovery of estrogen classic nuclear pathway, the membrane-initiated estrogen receptors and their signal transduction pathways.
Previously, epidemiologic data demonstrated that women had a higher risk of non-small cell lung cancer (NSCLC) compared with men after excluding smoking effect, and a lower risk of lung cancer mortality compared with that in breast cancer patients treated by antiestrogenic therapy. Similarly, the epidemiological studies of gastric cancer incidence indicate the higher gastric cancer in males than females prior to menopause, however, following menopause, there is no significant difference of incidence between females and males. In prostate cancer patients, the higher risk of gastric cancer has been reported, which is decreased when those patient were treated by antiestrogenic medicine. In breast cancer ER+ patients whose cancer, a significantly increased risk of subsequent gastric cancer was reported when the patients were treated by tamoxifen. In addition, ovariectomy (OVX) also significantly increases the risk of gastric cancer in females. Taken together, estrogen possibly plays an important role in the development of NSCLC and gastric cancers.
Three genes encoding estrogen-bound proteins have been identified: G-protein coupled estrogen receptor 1 (GPER1 or GPR30), estrogen receptor-α (ER-α) and estrogen receptor-β(ER-β), which have similar structural and functional domains, including activation function domain 1 (AF-1), a DNA binding domain (DBD), a dimerization domain and activation function domain 2 (AF-2), which is the ligand binding domain (LBD). ER-α and ER-β, both belonging to the nuclear super family of ligand-dependent transcription factors, have highly conserved DBD and LBD regions modulating the classical nuclear estrogen pathway. Insulin (IL) binds to insulin receptor (IR), stimulating the phosphorylation of insulin receptor substrate (IRS); that phosphorylated IRS interacts with dimer estrogen-ER complexes, which can then translocate into the nucleus and bond with estrogen response elements (ERE) sequence to regulate RNA transcription through the estrogen classical nuclear pathway. Bcl-2, a key member of anti-apoptosis family proteins, has been reported to have its over-expression linked to many kinds of cancers in human being. The promoter of Bcl-2 gene contains an ERE sequence, and Bcl-2 mRNA expression in MCF-7 cells has been found to be positively regulated by E2 (17β-estradiol, an estrogen) and inhibited by tamoxifen; and that the proliferation of MCF-7 cells is modulated by IL, and the sensitivity of these cells to tamoxifen is increased after the temporary removal of IL from culture medium or when IRS expression was transiently knocked down using IRS-specific siRNA.
ER-α and ER-β also regulate cell proliferation, matrix/migration, metabolism and glucose homeostasis through membrane-initiated estrogen signaling (MIES), associating with plasma membrane by palmitoylation interaction in their LBD. The previous studies on ER knockout mice indicate that ER-α is the dominant functional estrogen receptor, when compared with ER-β. Clinically, ER positive cancers are diagnosticated by the ER-α antibody. Three transcription variants of ER-α66, 46 and 36, have been found. ER-α36 contains a partial ligand binding domain and palmitoylation motif (445-453), and possessing a unique C-terminal 27 amino acid sequence in place of the typical 140 amino acids (456-595) of full-length ER-α. ER-α36 has been found to be located predominantly at plasma membrane using an ER-α36 specific antibody. Since ER-α36 lacks the AF-1 and AF-2 domains, and that it still contains the ability binding to membrane, moreover, it is found to be uniquely expressed in tamoxifen-resisted breast cancer cells and uterine endometria epithelia cancer cells, MIES modulated by membrane-bound ER-α36 is thought to be responsible for the resistance to the anti-estrogen therapy. The previous studies demonstrated that the expression of ER-α36 may be one of the factors affecting tumorigenesis in gastric cancer patients. Moreover, because previously known ER-α antibodies could not effectively recognize ER-α36, an ER-α36 specific antibody was developed by investigators. See e.g., Wang Z. Y. et al., Proc. Natl. Acad. Sci. USA. 2006, 103(24):9063-8. Using the ER-α36 specific antibody, investigators found that ER-α36 was overexpressed in triple negative breast cancers and in acquired or de novo tamoxifen-resistant ER-positive breast cancers. See Shi, et al., J. Clin. Oncol. 2009, 27(31), 3423-9.
GPER1 has been found predominately on endoplasmic reticular. It binds with E2 to modulate sensitive Ca2+ signal through G protein alpha subunit (Gas). E2-GPER1 complex actives Gas/PLC/inositol trisphosphate (IP3) pathway, which subsequently promotes Ca2+ release from Inositol 1, 4, 5-Trisphosphate Receptors (InsP3R) enhancing cell bioenergetics and apoptosis resistance. GPER1 knockout mice have been reported to exhibit impaired glucose tolerance, reduced bone growth, increased blood pressure, and eliminated estradiol-stimulated insulin release to cardiovascular, with no apparent effect on fertility. Thus, GPER1 involved in the modulation of estrogen-mediated metabolic signaling.
Raloxifene, lasofoxifene, bazedoxifene, or functional equivalent selective estrogen receptor modulators (SERM) were developed to prevent osteoporosis for postmenopausal women. A network meta-analysis of randomized controlled trials showed that these SERMs have a better benefit-risk ratio than that of aromatase inhibitors and tamoxifen (Mocellin, et al, J. Natl. Cancer Inst. 2016, 108(2):djv318).
There remains a need for a safe and effective treatment of cancers, in particular tamoxifen-resistant cancers.